Method of using a gene expression profile to determine cancer responsiveness to an anti-angiogenic agent
Methods and compositions are provided for the identification of a molecular diagnostic test for cancer. The test identifies cancer subtypes that are responsive to anti-angiogenesis therapeutics and enables classification of a patient within this subtype. The present invention can be used to determine whether patients with cancer are clinically responsive or non-responsive to a therapeutic regimen prior to administration of any anti-angiogenic agent. This test may be used in different cancer types and with different drugs that directly or indirectly affect angiogenesis or angiogenesis signalling. In addition, the present invention may be used as a prognostic indicator for certain cancer types. In particular, the present invention is directed to the use of certain combinations of predictive markers, wherein the expression of the predictive markers correlates with responsiveness or non-responsiveness to a therapeutic regimen.
1. A method of treating a subgroup of subjects from a population of subjects having ovarian cancer, prostate cancer, glioblastoma, or breast cancer comprising: (i) providing a subject from the population of subjects known to overexpress at least one gene relative to a pre-defined cut-off threshold value which separates a particular disease into a first phenotype that indicates responsiveness to an anti-angiogenic agent and a second phenotype that indicates resistance to the anti-angiogenic agent, wherein the at least one gene is selected from the group consisting of GJB2, MMP13, GFPT2, BICC1, CDH11, MRVI1, PMP22, COL11Al, IGFL2, LUM, NTM, BGN, COL3A1, COL10A1, RAB31, ANGPTL2, PLAU, COL8A1, MIR1245, POLD2, NKD2, FZD1, COPZ2, ITGA5, VGLL3, MMP14, VCAN, THBS2, RUNX2, TIMP3, SFRP2, COL1A2, COL5A2, SERPINF1, KIF26B, TNFAIP6, MMP2, FN1, ALPK2, CTSK, LOXL1, and FAP in a tumor sample from the subject; and (ii) administering the anti-angiogenic agent to the subject in an amount sufficient to inhibit angiogenesis in the cancer.
2. The method of claim 1 , wherein the method measures the level of mRNA, cRNA, cDNA, or protein of the at least one gene.
3. The method of claim 1 , wherein the cancer is ovarian cancer.
4. The method of claim 3 , wherein the method measures the level of mRNA, cRNA, cDNA, or protein of the one gene.
5. The method of claim 1 , wherein the anti-angiogenic agent is selected from VEGF pathway-targeted therapeutic agents, angiopoietin-TIE2 pathway inhibitors, endogenous angiogenic inhibitors, and immunomodulatory agents.
6. The method of claim 5 , wherein the VEGF pathway-targeted therapeutic agent(s) is chosen from bevacizumab (Avastin), afibercept (VEGF Trap), IMC-1121B (Ramucirumab), imatinib (Gleevec), sorafenib (Nexavar), gefitinib (Iressa), sunitinib (Sutent), erlotinib, tivozinib, cediranib (Recentin), pazopanib (Votrient), BIBF 1120 (Vargatef), dovitinib, semaxanib (Sugen), axitinib (AG013736), vandetanib (Zactima), nilotinib (Tasigna), dasatinib (Sprycel), vatalanib, motesanib, ABT-869, TKI-258, and a combination thereof.
7. The method of claim 6 , wherein the VEGF pathway-targeted therapeutic agent is bevacizumab.
8. The method of claim 1 , wherein the cancer is prostate cancer.
9. The method of claim 1 , wherein the cancer is glioblastoma.
10. The method of claim 1 , wherein the cancer is breast cancer.
11. A method of treating ovarian cancer, prostate cancer, glioblastoma, or breast cancer in a patient comprising administering an anti-angiogenic agent to the patient in an amount sufficient to inhibit angiogenesis in the cancer, wherein the patient is known to overexpress at least one gene relative to a pre-defined cut-off threshold value which separates a particular disease into a first phenotype that indicates responsiveness to the anti-angiogenic agent and a second phenotype that indicates resistance to the anti-angiogenic agent, wherein the at least one gene is selected from the group consisting of GJB2, MMP13, GFPT2, BICC1, CDH11, MRVI1, PMP22, COL11Al, IGFL2, LUM, NTM, BGN, COL3A1, COL10A1, RAB31, ANGPTL2, PLAU, COL8A1, MIR1245, POLD2, NKD2, FZD1, COPZ2, ITGA5, VGLL3, MMP14, VCAN, THBS2, RUNX2, TIMP3, SFRP2, COL1A2, COL5A2, SERPINF1, KIF26B, TNFAIP6, MMP2, FN1, ALPK2, CTSK, LOXL1, and FAP in a sample of the cancer.
12. The method of claim 11 , wherein the cancer is ovarian cancer.
13. The method of claim 12 , wherein the method measures the level of mRNA, cRNA, cDNA, or protein of the one gene.
14. The method of claim 11 , wherein the method measures the level of mRNA, cRNA, cDNA, or protein of the at least one gene.
15. The method of claim 11 , wherein the anti-angiogenic agent is selected from VEGF pathway-targeted therapeutic agents, angiopoietin-TIE2 pathway inhibitors, endogenous angiogenic inhibitors, and immunomodulatory agents.
16. The method of claim 15 , wherein the VEGF pathway-targeted therapeutic agent(s) is chosen from bevacizumab (Avastin), afibercept (VEGF Trap), IMC-1121B (Ramucirumab), imatinib (Gleevec), sorafenib (Nexavar), gefitinib (Iressa), sunitinib (Sutent), erlotinib, tivozinib, cediranib (Recentin), pazopanib (Votrient), BIBF 1120 (Vargatef), dovitinib, semaxanib (Sugen), axitinib (AG013736), vandetanib (Zactima), nilotinib (Tasigna), dasatinib (Sprycel), vatalanib, motesanib, ABT-869, TKI-258, and a combination thereof.
17. The method of claim 16 , wherein the VEGF pathway-targeted therapeutic agent is bevacizumab.
18. The method of claim 11 , wherein the patient is a human.
19. The method of claim 11 , wherein the cancer is prostate cancer.
20. The method of claim 11 , wherein the cancer is glioblastoma.
21. The method of claim 11 , wherein the cancer is breast cancer.